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Boosting metabolism with low USF1
Laurila et al. show that a deficiency of the transcription factor USF1 protects against obesity, insulin resistance, and cardiovascular disease. Even when fed a high-fat diet, USF1-deficient mice stayed lean and maintained a beneficial lipid profile with low triglycerides and high high-density lipoprotein (HDL) cholesterol. The mice had elevated energy expenditure because their brown adipose tissue was more active. In USF1-deficient mice, glucose and lipids were rapidly cleared from the circulation to be burned by brown fat. In humans, individuals with reduced USF1 expression also had higher plasma HDL cholesterol and lower triglycerides, and were more insulin-sensitive and less prone to hardening of the arteries. These findings identify USF1 as a potential therapeutic target for treating metabolic and cardiac diseases.
USF1 (upstream stimulatory factor 1) is a transcription factor associated with familial combined hyperlipidemia and coronary artery disease in humans. However, whether USF1 is beneficial or detrimental to cardiometabolic health has not been addressed. By inactivating USF1 in mice, we demonstrate protection against diet-induced dyslipidemia, obesity, insulin resistance, hepatic steatosis, and atherosclerosis. The favorable plasma lipid profile, including increased high-density lipoprotein cholesterol and decreased triglycerides, was coupled with increased energy expenditure due to activation of brown adipose tissue (BAT). Usf1 inactivation directs triglycerides from the circulation to BAT for combustion via a lipoprotein lipase–dependent mechanism, thus enhancing plasma triglyceride clearance. Mice lacking Usf1 displayed increased BAT-facilitated, diet-induced thermogenesis with up-regulation of mitochondrial respiratory chain complexes, as well as increased BAT activity even at thermoneutrality and after BAT sympathectomy. A direct effect of USF1 on BAT activation was demonstrated by an amplified adrenergic response in brown adipocytes after Usf1 silencing, and by augmented norepinephrine-induced thermogenesis in mice lacking Usf1. In humans, individuals carrying SNP (single-nucleotide polymorphism) alleles that reduced USF1 mRNA expression also displayed a beneficial cardiometabolic profile, featuring improved insulin sensitivity, a favorable lipid profile, and reduced atherosclerosis. Our findings identify a new molecular link between lipid metabolism and energy expenditure, and point to the potential of USF1 as a therapeutic target for cardiometabolic disease.
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